Lifitegrast (trade name Xiidra) is a drug for the treatment of keratoconjunctivitis sicca (dry eye syndrome). The chemical name of lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methyl sulfonyl)phenyl) propanoic acid. The molecular formula of lifitegrast is C29H24Cl2N2O7S and its molecular weight is 615.5. Lifitegrast is a white to off-white powder which is soluble in water and a formula as shown below:
It was originally developed by Shire in 2013. The Drug Administration (FDA) approval for Xiidra (lifitegrast ophthalmic solution) 5%, a twice-daily eye drop indicated for the treatment of the signs and symptoms of dry eye disease in adult patients on July 2016.
U.S. Pat. No. 8,080,562B2 reveals two approaches for general lifitegrast synthesis. IM1 or IM3 is reacted with IM4 in the presence of HATU as a coupling reagent to provide IM5 or IM5a. In the subsequent hydrolysis step, IM5 or IM5a is treated with HCl in dioxane to provide IM6. Next, the in situ generated benzofuranoyl chloride (from IM7) was combined with IM6 to afford IM8 (R1=Bn) or IM8a. Finally, lifitegrast is conducted by deprotection (i.e. removal of the Bn group by using hydrogenolysis). See Scheme 1 below.

U.S. Pat. No. 9,353,088B2 disclosed the hydrolysis of IM8 or IM8a by using sodium hydroxide as base to obtain lifitegrast. U.S. Pat. No. 8,378,105B2 disclosed the hydrolysis process by using acid (i.e. HCl) or base (i.e. NaOH) in presence of aprotic solvent (i.e. dioxane). U.S. Patent Application Publication No. 20150336939A1 also disclosed that the reaction mixture is biphasic during the hydrolysis. In addition, U.S. Pat. No. 8,871,935B2 disclosed the hydrogenolysis of an ester (IM8) with a palladium catalyst in presence of MeOH/THF (5:1) as solvent. Given this transfer hydrogenolysis process, the lifitegrast with high optical purity (98.5%) of (S)-enantiomer was obtained, as compared to 79%/o to 94.5% (S)-enantiomer optical purity obtained by hydrolysis of the corresponding methyl ester. See Scheme 2 below:

Despite the above described processes, there remains a need for the development of more efficient and improved processes for the preparation of lifitegrast. The present disclosure addresses this need and provides related advantages as well.